This application proposes Ian A. Cook, M.D., for a Mentored Clinical Scientist Development Award. The goal is to enable him to pursue a new research direction in factors influencing increased drug sensitivity in the elderly. The Award will permit Dr. Cook to acquire new skills and expertise to support this work (a) in Dr. Cook will apply his skills in quantitative neuroimaging and in quantitative electroencephalography (QEEG) to study the relationship of BBB function and cerebral white matter changes (WMC) to drug sensitivity in the elderly. His specific aims are (1) to examine the association between increased drug sensitivity and WMC, (2) to examine the role of specific apolipoprotein E (apo E) genotypes in modifying drug sensitivity, and (3) to use EEG changes induced by infusion of pharmacologic probes to examine alteration in the selective permeability of the BBB. He will test the following hypotheses: 1. the pharmacologic probe method will be a valid technique for in vivo assessment of BBB function 2. the presence of WMC will be associated with an increase in BBB permeability (large amounts of WMC will be associated with high permeability to the pharmacologic probes); 3. the apo E genotype will modify the impact of WMC; individuals with e3/3 genotype and little WMC will have the lowest permeability to pharmacologic probes while e4/4 genotype and large amounts of WMC will have the highest, and other states intermediate permeability. 4. A mode can combine these WMC and apo E factors to permit prediction of permeability to the probe method and associated sensitivity to drug effects. His three-phase project will assess BBB function with a pharmacologic probe in a total of 64 subjects: 59 elderly control subjects, and 5 with known BBB disruption. Entry of the probe molecule across the BBB into the brain will be detected by changes in QEEG measures of brain function. These data will be correlated with MRI-determined volumes of WMC, and compared with the clinical occurrence of increased medication sensitivity With the additional skills and experience acquired during the Award period, Dr. Cook will be well prepared to undertake independent and collaborative investigations, to expand his teaching roles, and to play a role in bridging basic science and clinical research within the Department.